The present invention relates to methods. compositions and solutions for treating human alopecia, including male pattern alopecia (androgenic alopecia) and alopecia areata, involving the use of a substance known as BRL-34915 and related 4-amino and 4-amido-substituted chromans, chromenes, and chromanols of Formula I, in association with a pharmaceutical carrier adapted for topical application.
European Patent Publication Nos. 76075, 91748, 93535, 95316, 107423, 120426, 120427, 126311, 126350, 126367, 138134 and 173848 describe classes of chromanols, chromenes and chromans having antihypertensive activity and that they are of potential use in the treatment of other cardiovascular disorders. Such disorders include congestive heart failure, engine, peripheral vascular disease and cerebral vascular disease.
Dermatologists recognize many different types of hair loss, the most common by far being "androgenic alopecia" wherein human males begin losing scalp hair at the temples and on the crown of the head as they get older while this type of hair loss is largely confined to males, hence its common name "male pattern baldness", it is not unknown in women.
Dr. Charles A. Chidsey, III and Dr. Guinter Kahn disclose and claim in U.S. Pat. No. 4,596,812 the use of minoxidil, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine, as a therapeutic agent to treat alopecia and arrest and reverse male pattern alopecia. See also U.S. Pat. No.4,139,619 which claims the use of minoxidil and related 6-amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidines as a means for (a) increasing the rate of growth of terminal hair, and (b) converting vellus hair to growth as terminal hair.
The use of retinoids alone or in combination with minoxidil and related substituted pyrimidines to increase the rate of hair growth is disclosed in PGT publication numbers US85/04577, PGT US83/02558 and PCT US82/02833.
The use of minoxidil sulphate (2,6,-diamino-4-(1-piperidinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt) as therapeutic agent to stimulate the rate of hair growth is disclosed in PCT Application US86/00073, filed 23 Jan. 1986. In addition, the induced relaxation of rabbit superior mesenteric artery smooth muscle by minoxidil sulphate and dependence on potassium permeability has been reported. See K. D. Meisheri, et al, "The Mechanisms of Vascular Smooth Muscle Relaxing Effects of Minoxidil Sulfate"; Smooth Muscle Function Symposium Proceedings: Official Satellite Symposium of the XXX Internation Congress of the International Union of Physiological Sciences, Banff Center, Banff, Canada, 1986, page 114, abstract W4-P5.
Notwithstanding the fact that nothing before the use of topical application of minoxidil had been found which was effective in preventing, let alone reversing, male pattern baldness, a good deal is known about various types of human hair and its growth patterns on various parts of the body.
For purposes of the present invention, we need only consider two types of hair, namely "terminal hairs" and "vellus hairs". Terminal hairs are coarse, pigmented, long hairs in which the bulb of the hair follicle is seated deep in the dermis. Vellus hairs, on the other hand, are fine, thin, non-pigmented short hairs in which the hair bulb is located superficially in the dermis. As alopecia progresses, a transition takes place in the area of approaching baldness wherein the hairs themselves are changing from the terminal to the vellus type.
Another factor that contributes to the end result is a change in the cycle of hair growth. All hair, both human and animal, passes through a life cycle that includes three phases, namely, (1) the anagen phase (2) the catagen phase and (3) the telogen phase. The anagen phase is the period of active hair growth and, insofar as scalp hair is concerned, this generally lasts from 3-5 years. The catagen phase is a short transitional phase between the anagen and telogen phases which, in the case of scalp hair, lasts only 1-2 weeks. The final phase is the telogen phase which, for all practical purposes, can be denominated by a "resting phase" where all growth ceases and the hair eventually is shed preparatory to the follicle commencing to grow a new one. Scalp hair in the telogen phase is also relatively short-lived, some 3-4 months elapsing before the hair is shed and a new one beings to grow.
Now, under normal hair growth conditions on the scalp, approximately 88% of the hairs are in the anagen phase, only 1% in catagen and the remainder in telogen. With the onset of male pattern baldness, a successively greater proportion of the hairs are in the telogen phase with correspondingly fewer in the active growth anagen phase.
The remaining result associated with alopecia is the severe diminution of hair follicles. A bald human subject will average only about 306 follicles per square centimeter, whereas, a non-bald one in the same age group (30-90 years) will still have an average of 460 follicles per square centimeter. This amounts to a one-third reduction in hair follicles which, when added to the increased proportion of vellus hair follicles and the increase number of hair follicles in telogen, is both significant and noticeable. It is written that approximately 50% of the hairs must be shed to produce visible thinning of scalp hair. It is thus a combination of these factors: (1) transition of hairs from terminal to vellus, (2) increased number of telogen hairs--some of which have been shed, and (3) loss of hair follicles (atrophy in Settel's description) that produces "baldness".
Now, while a good deal is known about the results of male pattern baldness, very little is known about its cause. About all that can be said is that the cause is felt to be genetic and hormonal in origin although as will be seen presently, the known prior art attempts to control it through hormone adjustment have been singularly unsuccessful.
At the present time, one known treatment for male pattern alopecia is hair transplantation. Plugs of skin containing hair are transplanted from areas of the scalp where hair is growing to bald areas with reasonable success; however, the procedure is a costly one in addition to being time-consuming and quite painful. Furthermore, the solution is inadequate from the standpoint that it becomes a practical, if not an economic, impossibility to replace but a tiny fraction of the hair present in a normal healthy head of hair.
As far as the other non-drug related approaches to the problem are concerned, they include such things as ultra-violet radiation, massage, psychiatric treatment and exercise therapy. None of these, however, has been generally accepted as being effective. Even such things as revascularization surgery and acupuncture have shown little, if any, promise.
By far, the most common approach to the problem of discovering a remedy for male pattern alopecia has been one of drug therapy. Many types of drugs ranging from vitamins to hormones have been tried and only recently has there been any indication whatsoever of even moderate success. For instance, it was felt for a long time that since an androgenic hormone was necessary for the development of male pattern baldness, that either systemic or topical application of an antiandrogenic hormone would provide the necessary inhibiting action to keep the baldness from occurring. The theory was promising but the results were uniformly disappointing.
The androgenic hormone testosterone was known, for example, to stimulate hair growth when applied topically to the deltoid area as well as when injected into the beard and pubic regions. Even oral administration was found to result in an increased hair growth in the beard and pubic areas as well as upon the trunk and extremities. While topical application to the arm causes increased hair growth, it is ineffective on the scalp and some thinning may even result. Heavy doses of testosterone have been even been known to cause male pattern alopecia.
Certain therapeutic agents have been known to induce hair growth in extensive areas of the trunk, limbs and even occasionally on the face. Such hair is of intermediate status in that it is coarser than vellus but not as coarse as terminal hair. The hair is generally quite short with a length of 3 cm being about maximum. Once the patient ceases taking the drug, the hair reverts to whatever is normal for the: particular site after six months to a year has elapsed. An example of such a drug is diphenylhydantoin which is an anticonvulsant drug widely used to control epileptic seizures. Hypertrichosis is frequently observed in epileptic children some two or three months after starting the drug and first becomes noticeable on the extensor aspects of the limbs and later on the trunk and face. The pattern is not unlike that sometimes caused by injury to the head. As for the hair, it is often shed when the drug is discontinued but may, in some circumstances, remain.
"Minoxidil", as was true with "Diazoxide", produced a good deal of hypertrichosis in patients to whom the drug was administered. See, for example, Journal of Laboratory and Clinical Medicine, Vol, 79, page 639, April, 1972; Circulation, Vol. 45. page 571, March 1972; and Clinical Pharmacy and Therapy, Vol. 13, page 436, 1972.
Streptomycin is another drug that has been found to produce hypertrichosis in much the same way as diphenylhydantoin when administered to children suffering from tuberculous meningitis. About the same effects were observed and the onset and reversal of the hypertrichosis in relation to the period of treatment with the antibiotic leave little, question but that it was the causative agent.
The compounds of the subject invention (Formula I) including, namely, 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b ]pyran-3-ol and trans-4-N-acetyl-ethylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]py ran-3-ol, are far different from diazoxide, and the 6-amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidines of U.S. Pat. No. 4,139,619 and 4,596,812.
The compound 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b ]pyran-3-ol, hereinafter to be referred to by the coined term "BRL-34915", was disclosed by J. M. Evans, R. E. Buckingham and K. Willcocks and it forms the subject matter among other similar compounds of U.S. Pat. No. 4,446,113 issued May 1, 1984. See Example 1 of U.S. Pat. 4,446,113. This compound, among others of Formula I, has been reported as a potent vasodilator anti-hypertensive agent and is currently under preclinical evaluation. It is a so-called direct acting "vasodilator" which, as the name implies, functions to dilate the peripheral vascular system. It is reported to act in a novel manner for an anti-hypertensive agent to cause hyperpolarisation of the cell membrane by activation of the outward conductance of potassium ions. The cell membrane is desensitized and the inward. movement of calcium is reduced in a way different from that of the calcium antagonist nifedipine See e.g., Br. J. Pharmac. (1986), 88, 121-128 and Br. J. Pharmac. (1986), 88, 103-111. It has not been reported to produce hypertrichosis so far as applicants are aware.
Minoxidil is a known vasodilator. Following reports of the use of minoxidil and related compounds to stimulate hair growth, and as a treatment of male pattern alopecia, other vasodilators including "viprostol" and "diazoxide" are reported as being evaluated by others to stimulate hair growth. See for example U.S. Pat. Nos. 4,431,833 and 4,311,707; European Patent 027,665 (published 04/29/81).
Vasodilators as a general class of therapeutic agents have, so far as applicants are aware, never proven effective to grow hair on the scalp as a result of topical application thereof to bald areas.
It is, therefore, the principal object of the present invention to provide a novel, unobvious and effective treatment for male pattern baldness.
Another object of the invention forming the subject matter hereof is to provide a method of treating certain types of baldness in humans that is compatible with various types of therapeutic agents or carriers and, therefore, would appear to be combinable with those which, by themselves. demonstrates some therapeutic activity such as, for example, microemulsion creams containing estradiol and oxandrolone.
Still another objective is the provision of a treatment for alopecia which, while effective for its intended purpose, is apparently non-toxic and relatively free of unwanted side effects.
An additional object of the invention herein disclosed and claimed is to provide a method for treating baldness in men which comprises application of a compound of Formula I by the patient himself under medical supervision no more stringent than that demanded for other topically-administered therapeutic agents.
Other objects of the invention are to provide a treatment for male pattern alopecia which is safe, simple, painless, cosmetic in the sense of being invisible, easy to apply and quite inexpensive when compared with hair transplanted and the like.
Further objects will be in part apparent and in part pointed out specifical hereinafter in connection with the detailed description of the invention which follows.
Dermatologists and others were well aware of the fact that prolonged vasodilation of certain areas of the human body other than the scalp sometimes resulted in increased hair growth even in the absence of any vasodilating therapeutic agent. For instance, increased hair growth around surgical scars is not uncommon. Similarly, arteriovenous fistula have been known to result in increased vascularity accompanied by enhanced hair growth. Externally-induced vasodilation of the skin, such as, for example, by repeated biting of the limbs by mental retardates and localized stimulation of the shoulders by water carriers has been noted to bring on hypertrichosis in the affected areas. Be that as it may, similar techniques such as continued periodic massage of the scalp have been found totally ineffective as a means for restoring lost hair growth to the scalp. Scar tissue on the scalp inhibits rather than promotes hair growth.